Biology subjects

Urfer, S.

Publications and source records attributed to Urfer, S..

3 recordsLinked to original sources

bioRxiv2023

The hydrogen sulfide donor sodium thiosulfate limits inflammation but aggravate smooth muscle cells apoptosis and aneurysm progression in a mouse model of abdominal aortic aneurysm

IntroThe prevalence of abdominal aortic aneurysm (AAA) is constantly progressing with the aging of the global population. AAA rupture has a devastating 80% mortality rate and there is no treatment to slow-down AAA progression. Hydrogen sulfide (H2S) is a ubiquitous redox-modifying gasotransmitter produced in the cardiovascular system via the reverse trans-sulfuration pathway by cystathionine {gamma}-lyase (CSE). H2S has protective properties on the cardiovascular system, including anti-inflammatory and antioxidant effects. Here, we hypothesized that sodium thiosulfate (STS), a clinically relevant source of H2S, would limit AAA growth. Methods8-12 weeks old male WT or Cse-/- mice on a C57BL/6J genetic background were submitted to a model of AAA by topical elastase application on the abdominal aorta and {beta}-aminopropionitrile fumarate treatment in the drinking water for 2 weeks post-op. Sodium thiosulfate (STS) was given via the drinking water post-op until aorta collection. In vitro experiments were conducted to assess the effect of STS and pro-inflammatory cytokines interleukin-1 {beta} and 6 and tumor necrosis factor on primary human vascular smooth muscle cell (VSMC). ResultsSurprisingly, STS increased elastin degradation, AAA size and rupture, despite reducing infiltration of macrophages, antigen-presenting cells and lymphocytes in WT mice. Conversely, Cse-/- mice with impaired H2S production developed smaller AAA than WT mice despite increased infiltration of immune cells. STS reduced VSMC coverage, possibly lowered VSMC proliferation, and promoted VSMC loss and extracellular matrix (ECM) breakdown. In vitro, STS aggravated pro-inflammatory cytokine-induced VSMCs apoptosis. ConclusionSTS has a paradoxical effect on AAA growth, reducing inflammation while simultaneously impeding favorable vascular remodeling, resulting in bigger AAA in a model of periadventitial elastase. This study identifies a negative effect of H2S on VSMC in this environment, highlighting the complex role of H2S in AAA progression. The deleterious effect of STS on AAA progression is significant, especially given the growing use of STS in clinical settings for various indications.

physiology↗

bioRxiv2022

Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh Syndrome

Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological aging process. Rapamycin, a drug that increases lifespan and health during normative aging also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh Syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh Syndrome. Here we show that another drug that extends lifespan and delays normative aging in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of mTOR inhibition. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression. This study provides the first evidence that alteration of the gut microbiome may impact severe mitochondrial disease and provides further support for the model that biological aging and severe mitochondrial disorders share underlying common mechanisms.

biochemistry↗

bioRxiv2021

Sodium Thiosulfate acts as an H2S mimetic to prevent intimal hyperplasia via inhibition of tubulin polymerization

BackgroundIntimal hyperplasia (IH) remains a major limitation in the long-term success of any type of revascularization. IH is due to vascular smooth muscle cell (VSMC) dedifferentiation, proliferation and migration. The gasotransmitter Hydrogen Sulfide (H2S) inhibits IH in pre-clinical models. However, there is currently no clinically approved H2S donor. Here we used sodium thiosulfate (STS), a clinically-approved source of sulfur, to limit IH. MethodsHypercholesterolemic LDLR deleted (LDLR-/-), WT or CSE-/- male mice randomly treated with 4g/L STS in the water bottle were submitted to focal carotid artery stenosis to induce IH. Human vein segments were maintained in culture for 7 days to induce IH. Further in vitro studies were conducted in primary human vascular smooth muscle cell (VSMC). FindingsSTS inhibited IH in mice and in human vein segments. STS inhibited cell proliferation in the carotid artery wall and in human vein segments. STS increased polysulfides in vivo and protein persulfidation in vitro, which correlated with microtubule depolymerization, cell cycle arrest and reduced VSMC migration and proliferation. InterpretationSTS, a drug used for the treatment of cyanide poisoning and calciphylaxis, protects against IH in a mouse model of arterial restenosis and in human vein segments. STS acts as an H2S donor to limit VSMC migration and proliferation via microtubule depolymerization. FundingThis work was supported by the Swiss National Science Foundation (grant FN-310030_176158 to FA and SD and PZ00P3-185927 to AL); the Novartis Foundation to FA; and the Union des Societes Suisses des Maladies Vasculaires to SD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/459573v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@c98479org.highwire.dtl.DTLVardef@1863f0org.highwire.dtl.DTLVardef@1492ad7org.highwire.dtl.DTLVardef@9bca8a_HPS_FORMAT_FIGEXP M_FIG C_FIG Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIntimal hyperplasia (IH) is a complex process leading to vessel restenosis, a major complication following cardiovascular surgeries and angioplasties. Therapies to limit IH are currently limited. Pre-clinical studies suggest that hydrogen sulfide (H2S), an endogenous gasotransmitter, limits restenosis. However, despite these potent cardiovascular benefits in pre-clinical studies, H2S-based therapeutics are not available yet. Sodium thiosulfate (Na2S2O3) is an FDA-approved drug used for the treatment of cyanide poisoning and calciphylaxis, a rare condition of vascular calcification affecting patients with end-stage renal disease. Evidence suggest that thiosulfate may generate H2S in vivo in pre-clinical studies. Added value of this studyHere, we demonstrate that STS inhibit IH in a surgical mouse model of IH and in an ex vivo model of IH in human vein culture. We further found that STS increases circulating polysulfide levels in vivo and inhibits IH via decreased cell proliferation via disruption of the normal cells cytoskeleton. Finally, using CSE knockout mice, the main enzyme responsible for H2S production in the vasculature, we found that STS rescue these mice from accelerated IF formation. Implications of all the available evidenceThese findings suggest that STS holds strong translational potentials to limit IH following vascular surgeries and should be investigated further.

physiology↗